The perception of odorous molecules begins in the olfactory epithelium when odorant ligands bind to molecular receptors expressed on the cilia of the olfactory sensory neurons (OSNs). Buck and Axel (1991) were the first to describe the large family of genes coding for the odorant receptors, now known to number ~1,200 in mice. An OSN expresses only 1 odorant receptor. OSNs expressing the same receptor do not cluster together but rather are broadly distributed across the epithelium. Thus the olfactory epitheium is a complex mosaic of neurons each of which expresses only 1 of 1,200 possible odorant receptors. As their axons exit the epithelium they initially fasciculate with nearest neighbors, no necessarily with axons from other neurons expressing the same odorant receptor. However, as they progress over the surface of the olfactory bulb and a point of glomerular convergence, the axons undergo a profound topographical reorganization such that all of the axons coming from neurons expressing the same odorant receptor converge into only 2/3 glomeruli/olfactory bulb. This process of reorganization of axons and convergence into specific glomeruli poses a significant wiring problem, perhaps the most complex wiring problem found among sensory systems. It is widely accepted that the odorant receptors themselves contribute to the convergence of homotypic axons but the process of fasciculation and axon behavior remains poorly understood. Despite a concerted effort to identify the molecular substrates of sensory axon growth, coalescence and targeting, we remain woefully ignorant of the most fundamental aspects of OSN axon organization: When does the initial fasciculation of axons begin, the processes of defasciculation and reorganization? When do homotypic axons expressing the same odorant receptor show evidence of irreversible adhesion? What is the relationship of individual axons to the olfactory ensheathing cells along the course of the olfactory nerve and olfactory nerve layer? How are growth cones distributed and organized in the fascicles both during early development when the pathway is established and in the adult during ongoing axogenesis? Where and when is the odorant receptor mRNA expressed in axons? Does local axonal translation of mRNA occur, and if so under what conditions and where? To begin addressing these significant gaps in our knowledge we are proposing 3 specific aims: Aim 1 - Test the hypothesis that adhesion of homotypic axons does not occur until they are proximal to the site of glomerular convergence; Aim 2 - Test the hypothesis that the growth cones of olfactory sensory neuron axons are not homogeneously distributed within fascicles; and Aim 3 - Test the hypotheses that odorant receptor mRNAs and the translational components are locally compartmentalized in the olfactory nerve/sensory axons. PUBLIC HEALTH RELEVANCE: Despite its inherent complexity, the olfactory nerve pathway is regenerated and remodeled throughout life as a result of ongoing neurogenesis of olfactory sensory neurons in the epithelium. This is the only site in the central nervous system that has exhibited such a profound capacity for the successful regeneration of axons - both axon extension and specificity of targeting are retained throughout life. Understanding the properties that allow the successful replacement of this axonal pathway will provide better insight into the structure-function relationships in olfaction and lead to improvements in strategies for treating traumatic and genetic perturbations of neuronal populations and axonal pathways elsewhere in brain.